Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa 52242Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21287

Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa 52242Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21287

Abstract

Genome-wide association studies (GWAS) have been widely used for identifying common variants associated with complex diseases. Traditional analysis of GWAS typically examines one marker at a time, usually single nucleotide polymorphisms (SNPs), to identify individual variants associated with a disease. However, due to the small effect sizes of common variants, the power to detect individual risk variants is generally low. As a complementary approach to SNP-level analysis, a variety of gene-based association tests have been proposed. However, the power of existing gene-based tests is often dependent on the underlying genetic models, and it is not known a priori which test is optimal. Here we propose a combined association test (COMBAT) for genes, which incorporates strengths from existing gene-based tests and shows higher overall performance than any individual test. Our method does not require raw genotype or phenotype data, but needs only SNP-level P-values and correlations between SNPs from ancestry-matched samples. Extensive simulations showed that COMBAT has an appropriate type I error rate, maintains higher power across a wide range of genetic models, and is more robust than any individual gene-based test. We further demonstrated the superior performance of COMBAT over several other gene-based tests through reanalysis of the meta-analytic results of GWAS for bipolar disorder. Our method allows for the more powerful application of gene-based analysis to complex diseases, which will have broad use given that GWAS summary results are increasingly publicly available.

Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa 52242Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21287

Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa 52242Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21287

Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa 52242Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21287

Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa 52242Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21287

The Genetics Society of America (GSA), founded in 1931, is the professional membership organization for scientific researchers and educators in the field of genetics. Our members work to advance knowledge in the basic mechanisms of inheritance, from the molecular to the population level.